Her2 Chimeric Antigen Receptor Expressing T Cells in Advanced Sarcoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2015 by Baylor College of Medicine
Sponsor:
Collaborators:
Texas Children's Hospital
The Methodist Hospital System
Center for Cell and Gene Therapy, Baylor College of Medicine
Information provided by (Responsible Party):
Nabil Ahmed, Baylor College of Medicine
ClinicalTrials.gov Identifier:
NCT00902044
First received: May 13, 2009
Last updated: May 15, 2015
Last verified: May 2015

May 13, 2009
May 15, 2015
July 2009
July 2015   (final data collection date for primary outcome measure)
  • Number of patients with dose limiting toxicity after one injection of HER2-specific T cells [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]
    To determine the safety of one intravenous injection of autologous T cells expressing HER2-specific chimeric antigen receptor (CAR) in patients with advanced HER2-positive sarcoma.
  • Number of patients with dose limiting toxicity after one injection of HER2-specific T cells after receiving lymphodepleting chemotherapy [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]
    To determine the safety of one intravenous injection of 1x10^8/m^2 autologous T cells after lymphodepleting chemotherapy.
To determine the safety of one intravenous injection of autologous T cells expressing HER2-specific chimeric antigen receptor (CAR) in patients with advanced HER2-positive osteosarcoma. [ Time Frame: 15 years ] [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT00902044 on ClinicalTrials.gov Archive Site
  • Frequency of HER2-specific T cells pre and post injection [ Time Frame: 15 years ] [ Designated as safety issue: No ]
    To assess the in vivo persistence of infused T cells using immunoassays and transgene detection
  • Change in tumor size from pre to post injection [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
    To assess the anti-tumor effects of the infused HER2-specific T cells
  • To assess the in vivo persistence of infused T cells using immunoassays and transgene detection [ Time Frame: 15 years ] [ Designated as safety issue: No ]
  • To assess the anti-tumor effects of the infused CAR-CTL [ Time Frame: 15 years ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Her2 Chimeric Antigen Receptor Expressing T Cells in Advanced Sarcoma
Administration of Her2 Chimeric Antigen Receptor Expressing T Cells for Subjects With Advanced Sarcoma (HEROS)

Patients have a type of cancer called sarcoma. The sarcoma has come back after treatment. Because there is no standard treatment for the patients cancer at this time or because the currently used treatments do not work fully in all cases, patients are being asked to volunteer to take part in a gene transfer research study using special immune cells.

The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting disease: antibodies and T cells. We hope that both will work better together. Antibodies are proteins that protect the body from diseases caused by germs or toxic substances. They work by binding those germs or substances, which stops them from growing or exerting their toxic effects. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells or cells that are infected with germs. Both antibodies and T cells have been used to treat patients with cancers: they both have shown promise, but have not been strong enough to cure most patients.

We have found from previous research that we can put a new gene into T cells that will make them recognize cancer cells and kill them. We now want to see if we can put a new gene in these cells that will let the T cells recognize and kill sarcoma cells. The new gene that we will put in makes an antibody specific for HER2 (Human Epidermal Growth Factor Receptor 2) that binds to sarcoma cells. In addition it contains CD28, which stimulated T cells and make them last longer.

In other clinical studies using T cells, some investigators found that giving chemotherapy before the T cell infusion can improve the amount of time the T cells stay in the body and therefore the effect the T cells can have. Giving chemotherapy before a T cell infusion is called lymphodepletion since the chemotherapy is specifically chosen to decrease the number of lymphocytes in the body. Decreasing the number of patient's lymphocytes first should allow the T cells we infuse to expand and stay longer in your body, and potentially kill cancer cells more effectively.

We will use fludarabine or the combination of cyclophosphamide and fludarabine as the chemotherapy agents for lymphodepletion. Cyclophosphamide and fludarabine are the chemotherapy agents most commonly used for lymphodepletion in immunotherapy clinical trials.

The purpose of this study is to find the largest safe dose of chimeric T cells, to learn what the side effects are, and to see whether this therapy might help patients with sarcoma. Another purpose is to see if it is safe to give HER2-CD28 T cells after lymphodepleting chemotherapy.

Because the cells have a new gene in them the patient will be followed for a total of 15 years to see if there are any long term side effects of gene transfer.

When the patient is enrolled on this study, they will be assigned a dose of HER2-CD28 T cells. Depending on which dose level they are assigned, they will receive one of the following:

HER2-CD28 T cells and fludarabine (patient will receive fludarabine for 5 days followed by injection of HER2-CD28 T cells)

OR

HER2-CD28 T cells, fludarabine and cyclophosphamide (patient will receive cyclophosphamide for 2 days and then will receive fludarabine for 5 days before receiving the HER2-CD28 T cells).

The HER2-CD28 T cells will be given into the vein through an IV line. The injection will take between 1 and 10 minutes. The patient will be followed in the clinic after the injection for 1 to 4 hours.

Each patient will be followed for 6 weeks after the T-cell infusion for evaluation of toxicity. They will have standard tests and procedures as well as research blood draws.

If the patient has stable disease (the tumor did not grow) or there is a reduction in the size of the tumor on imaging studies after the T-cell infusion, they can receive additional doses of the T cells at 6 to 12 weeks intervals.

Interventional
Phase 1
Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Sarcoma
  • Genetic: Autologous HER2-specific T cells

    Each patient will receive one intravenous injection of autologous HER2-specific T cells at one of the dose levels.

    If the patient has stable disease or a reduction in the size of the tumor they can receive up to 6 additional doses of T cells.

  • Drug: Fludarabine

    Fludarabine will be administered for 5 days prior to the T cells

    The dose:

    >10 kg: 25 mg/m2/day;

    <10 kg: 1 mg/kg/day IV over 30 minutes

  • Drug: Cyclophosphamide

    Cyclophosphamide will be administered for 2 days and then fludarabine will be given for the next 5 days and then the T cells will be administered

    Cyclophosphamide Dose:

    60 mg/kg/day IV over 1 hour (with Mesna and IV hydration)

    Fludarabine Dose:

    >10 kg: 25 mg/m2/day; <10 kg: 1 mg/kg/day IV over 30 minutes

    Other Name: Cytoxan
  • Experimental: Autologous HER2-specific T cells

    THIS ARM IS CLOSED

    Dose Level 1: 1x10^4 cells/m2

    Dose Level 2: 3x10^4 cells/m2

    Dose Level 3: 1x10^5 cells/m2 (NOT BEING USED)

    Dose Level 4: 3x10^5 cells/m2 (NOT BEING USED)

    Dose Level 5: 1x10^6 cells/m2

    Dose Level 6: 3x10^6 cells/m2

    Dose Level 7: 1x10^7 cells/m2

    Dose Level 8: 3x10^7 cells/m2

    Dose Level 9: 1x10^8 cells/m2

    Intervention: Genetic: Autologous HER2-specific T cells
  • Experimental: Autologous HER2-specific T cells + fludarabine
    Dose Level 9A: fludarabine followed by 1x10^8 cells/m^2
    Interventions:
    • Genetic: Autologous HER2-specific T cells
    • Drug: Fludarabine
  • Experimental: Autologous HER2-specific T cells+fludarabine+cyclophosphamide
    Dose Level 9B: fludarabine + cyclophosphamide followed by 1x10^8 cells/m^2
    Interventions:
    • Genetic: Autologous HER2-specific T cells
    • Drug: Fludarabine
    • Drug: Cyclophosphamide
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
36
July 2030
July 2015   (final data collection date for primary outcome measure)

INCLUSION CRITERIA:

Procurement Eligibility:

  1. Diagnosis of refractory HER2-positive sarcoma or metastatic HER2-positive osteosarcoma, not treatable by surgical resection.
  2. Karnofsky/Lansky score of 50 or greater
  3. Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent.

Treatment Eligibility:

  1. Diagnosis of refractory HER2-positive sarcoma or metastatic HER2-positive sarcoma, not treatable by surgical resection and with disease progression after receiving at least one prior systemic therapy.
  2. Recovered from the acute toxic effects of all prior chemotherapy at least 4 weeks before entering this study.
  3. Normal ECHO (Left ventricular ejection fraction (LVEF) has to be within normal, institutional limits)
  4. Life expectancy 6 weeks or greater
  5. Karnofsky/Lansky score of 50 or greater
  6. Bilirubin 3x or less, AST 5x or less, Serum creatinine 2x upper limit of normal or less, Hgb 9.0 g/dl or greater, WBC greater than 2,000/ul, ANC greater than 1,000/ul, platelets greater than 100,000/ul. Creatinine clearance is needed for patients with creatinine greater than 1.5 times upper limit of normal.
  7. Pulse oximetry of 90% or greater on room air
  8. Sexually active patients must be willing to utilize one of the more effective birth control methods for 6 months after the CTL infusion. Male partner should use a condom
  9. Available autologous transduced T lymphocytes with 15% or more expression of HER2 CAR as determined by flow-cytometry and killing of HER2-positive targets 20 % or greater in cytotoxicity assay.
  10. Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent

EXCLUSION CRITERIA:

At time of Procurement:

  1. Known HIV positivity
  2. Severe previous toxicity from cyclophosphamide or fludarabine

At time of Treatment:

  1. Severe intercurrent infection
  2. Known HIV positivity
  3. Pregnant or lactating
  4. History of hypersensitivity reactions to murine protein-containing products
  5. Severe previous toxicity from cyclophosphamide or fludarabine
Both
Not Provided
No
Contact: Nabil M Ahmed, MD 834-824-4611 nmahmed@txch.org
Contact: Catherine Perera 832-824-4594 csperera@txch.org
United States
 
NCT00902044
24489-HEROS, HEROS
Yes
Nabil Ahmed, Baylor College of Medicine
Baylor College of Medicine
  • Texas Children's Hospital
  • The Methodist Hospital System
  • Center for Cell and Gene Therapy, Baylor College of Medicine
Principal Investigator: Nabil M Ahmed, MD Baylor College of Medicine/Texas Children's Hospital
Baylor College of Medicine
May 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP